Methods and compositions for treating thyroid-related medical conditions with reduced folates

ABSTRACT

The present invention provides methods and compositions for treating thyroid-related medical conditions. Many thyroid-related medical conditions exist that go undiagnosed and untreated. These conditions may be prevented and treated with reduced folates and vitamin B12. Administration of reduced folates and vitamin B12 will prevent or treat cerebrospinal folate deficiency, which is linked to thyroid-related medical conditions. Administration of reduced folates and vitamin B12 will also prevent or treat conditions associated with masked megaloblastic anemia and hypothyroidism, and other conditions brought upon through improper thyroid function. Additionally, it is commonplace to treat many thyroid conditions with anti-thyroid drugs or thyroid stimulating drugs. This practice alone is also responsible for causing, or not beneficially addressing, adverse conditions that can be prevented or treated through the methods and compositions discussed herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Ser. No. 61/270,615 filed onJul. 10, 2009 and Provisional application No. 61/270,741 filed on Jul.13, 2009.

BACKGROUND

Developmental problems associated with folic acid deficiency are wellknown in the art. Perhaps neural tube defects in fetuses are the mostcommon problem associated with folate deficiency. Expecting mothers areroutinely placed on a folic acid regimen. Additionally, nursing mothersare also supplemented with folic acid to continue to provide nutritionto the newborn. During the prenatal and perinatal periods, folate isessential for adequate enclosure of the neural tube by dermal tissues.In recent studies, it has been shown that women with increased levels ofplasma homocysteine and decreased levels of erythrocyte folate have agreater risk of having an offspring with a neural tube defect. It isbelieved that during the early stages of pregnancy (prior to thedevelopment of the placenta) transport of folates to the fetus isprimarily performed by the maternal erythrocytes. Inadequate folatelevels in maternal erythrocytes are a significant factor in the lack ofprogression of neural tube closure in utero.

Folate helps produce and maintain new cells; this is criticallyimportant in cells with rapid growth that undergo frequent cell divisionsuch as in infancy and pregnancy. Folate is needed to form DNA and RNA,and both adults and children need folate to make normal red blood cells.It is essential that folates are part of the daily nutritionalconsumption for adequate human health.

Folates also play a critical role in the reduction of plasmahomocysteine levels. An increased amount of homocysteine in the plasmahas been associated with heart disease. Folates have been shown toreduce the calcification of plaques during an acute ischemic attack;thereby reducing the long-term effects of cardiovascular disease. Thus,folates are major components of cardiovascular functionality.

Folate is an essential water-soluble B. vitamin that occurs naturally infood. As a result of these important metabolic activities, severaldietary derivatives of folate are manufactured as supplements:

Although most of the derivatives are capable of becoming converted intothe metabolically active form (6S) 5-methyltetrahydrofolate, the enzymekinetics of such conversion can differ dramatically as well as theabsorption rate and it is these differences that are important indetermining the hierarchy of performance.

Folates are a group of pteroyglutamate acids that become structurallyand functionally altered when reduced (adding electrons) or oxidized(removing electrons). In humans, folates are absorbed most readily as5-methyltetrahydrofolate and it is the principal circulating form offolate. Other derivatives are hydrolyzed in the intestinal jejunum andthe liver to the active form with an intermediate stable form(5,10-methylenetetrahydrofolate).

5-methyltetrahydrofolate is the predominant form of folate in thecirculatory system and is the type of folate that can cross theblood-brain barrier. 5-methyltetrahydrofolate is critical for braindevelopment and normal mental health.

The endocrine system is a system of glands, each of which secretes atype of hormone into the bloodstream to regulate the body. The endocrinesystem is an information signal system like the nervous system. Hormonesregulate many functions of an organism, including mood, growth anddevelopment, tissue function, and metabolism.

Thyroid-related medical conditions, and medications that are used inconnection with thyroid conditions, are known to cause hematologicalissues in individuals, as well as in fetuses of such individuals who maybe pregnant, or the children who receive breast milk from suchindividuals who have thyroid-related medical conditions and/or who areon thyroid medication. In addition, these thyroid-related medicalconditions, and the medications that are used in connection with thyroidconditions, are known to cause adverse hepatic conditions regarding theliver, as well as having an adverse impact on other organs. Moreover, inaddition to those persons who have thyroid-related medical conditions orwho are taking medications for thyroid conditions, environmentalconditions, and environmental contaminants are also known to impact thethyroid system of an individual, as well as the fetus of such individualor child nursing from such individual. Thus, the thyroid system can beimpacted by thyroid-related medical conditions that develop within one'sown body, by certain medications, and by the environment.

Typically, thyroid conditions are treated with medication to address thethyroid condition and bring the patient to a euthyroid state. That isthe focus of the medical community and pharmaceutical community.However, bringing an individual to a euthyroid state does notsufficiently address the adverse conditions associated with low folate,as well as vitamin B12, and specifically low cerebrospinal folate. Themedical and pharmaceutical communities have not been able tosufficiently address the further complications the thyroid-relatedmedical conditions, and/or the medications that are used in connectionwith thyroid conditions, cause. For instance, anti-thyroid drugs areknown to cause (a) numerous blood disorders (including, but not limitedto, megaloblastic anemia, pancytopenia, aplastic anemia, neutropenia,agranulocytosis, thrombocytopenia, and leukopenia), (b) bone marrowsuppression, and (c) hepatic dysfunction. In addition, thyroid-relatedmedical conditions are known to cause similar conditions. For instance,hypothyroidism is known to cause iron, folate and/or vitamin B12deficiencies, which with respect to folate or vitamin B12 deficiencies,can cause “macrocytic” or “megaloblastic” hematological conditionsleading, in some cases, to bone marrow suppression and hepaticdysfunction, as well as dysfunction in other organs (polyglandularfailure syndrome for instance).

Even further, autoimmune conditions like chronic autoimmune thyroiditisand Hashimoto's thyroiditis associated with pernicious anemia can causeeven further vitamin B12 deficiencies that will not be corrected solelyby thyroid hormone replacement, but also require specific vitamin B12supplementation. Moreover, additional conditions that complicate theclinical picture are (1) “masked megaloblastic anemia” conditions thatcan arise from simultaneous iron and folate/vitamin B12 deficiencies,(2) lack of vitamin B12 which is critical in the metabolic pathway ofconverting folate into its biologically useful form, and (3)“polymorphisms” that are commonplace. For instance, themethylenetetrahydrofolate (MTHFR) polymorphism is very common, by someaccounts up to 40% of the U.S. population. As a result, some individualsare naturally more susceptible to having cerebrospinal folate issues, orancillary folate and/or vitamin B12 issues, than others based on whetheror not they have the polymorphism. Yet, notwithstanding the foregoing,thyroid-related medical conditions and drugs that are used to treatthyroid conditions are not augmented with suitable folate and B12supplementation protocols sufficient to prevent or ameliorate theadverse effects of low cerebrospinal folate.

FIELD OF INVENTION

This invention is generally in the field of treating thyroid conditionswith a folate and vitamin B12. Folate is a critical vitamin that isrequired for proper nutrition. Folate is important in forming DNA andRNA, therefore it is critical in cells that are growing or undergofrequent cell division. Folate deficiencies have led to harmful andserious health conditions in children as well as in adults. As a result,folate is especially important for pregnant mothers, nursing mothers andnewborns.

What has previously been unknown, or at least underappreciated, is therelationship between the thyroid and levels of folate, as well asvitamin B12, in the blood. Hypothyroid individuals have been found tosuffer folate, as well as, vitamin B12 deficiencies; and as such, theyare prone to the other problems that are also associated with low folatelevels. It is now discovered that conditions of hypothyroidism have ledto folate deficiencies in cerebrospinal fluid. There has been a newlydiscovered case involving the treatment of hyperthyroidism that has alsoled to folate deficiencies in cerebrospinal fluid. This is because thedrugs that are taken to treat hyperthyroidism suppress the thyroid andin some cases have suppressed it to the extent that it leads tohypothyroidism and folate deficiencies in cerebrospinal fluid. Inaddition, these anti-thyroid drugs can cause adverse hematological andhepatic conditions that can also contribute to deficiencies in folate,as well as vitamin B12, leading to cerebrospinal folate deficiency.

This surprising discovery has led to the present invention. Providingindividuals, who have had or are at risk of having thyroid-relatedmedical conditions, with folate and vitamin B12 has shown tobeneficially address and alleviate adverse outcomes associated with lowfolate in cerebrospinal fluid. The present invention also addressesthose who must take anti-thyroid drugs or thyroid stimulating drugs orhormones. Supplementation with folates and vitamin B12 along with eitheranti-thyroid drugs or thyroid stimulating drugs can provide a bettermeans of preventing and/or treating folate deficiencies and theassociated problems from such deficiencies.

This invention will help prevent and further help diagnose the cause offolate deficiencies in some individuals, as thyroid-related medicalconditions are presently not part of the focus of the medical andpharmaceutical communities. Further, leading researchers in the field ofcerebrospinal folate deficiency have mainly focused on antibodiesattacking the folate receptor or mitochondrial defects as the cause ofcerebrospinal folate deficiency.

There is clearly a need to make the relationship between thyroidfunction and folate deficiencies in cerebrospinal fluid known so that itis may be prevented and treated. This invention addresses that need.

SUMMARY OF THE INVENTION

The present invention provides methods and compositions for preventingand/or treating people with thyroid-related medical conditions fromdeveloping problems associated with folate deficiencies. In someembodiments, the present invention provides a method of administeringfolate to people with thyroid-related medical conditions. In someembodiments, the present invention provides a method of administeringfolate and vitamin B12 to people with thyroid-related medicalconditions. In some embodiments, the present invention further providesa method of administering a reduced folate to people withthyroid-related medical conditions. In some embodiments, the presentinvention further provides a method of administering a reduced folateand vitamin B12 to people with thyroid-related medical conditions. Yetin another embodiment, the present invention further provides a methodof administering folinic acid and vitamin B12 to people withthyroid-related medical conditions. And in some embodiments theadministration of folate and vitamin B12 will treat or preventcerebrospinal folate deficiency, masked megaloblastic anemia, othermacrocytic anemias (which include anemias that may be masked macrocyticanemias), or hepatic dysfunction. In some embodiments, the presentinvention will include the administration of folate and vitamin B12 andwill be coupled with the administration of iron. Other embodiments willinclude the administration of L-carnitine and/or calcium and/or vitaminD along with the administration of folate and vitamin B12. With respectto calcium and vitamin D, these are preferred embodiments that alsoaddress parathyroid hormone deficiencies.

In some embodiments, the present invention provides a method ofadministering folate and vitamin B12 to people with hypothyroidism orhyperthyroidism. In other embodiments, the present invention provides amethod of administering folate and vitamin B12 to people that have beentreated with radioactive iodine, or who have had surgery on or relatedto their thyroid, or who have had any procedure that has reduced thesize or activity of their thyroid gland. In another embodiment, thepresent invention provides a method of administering folate and vitaminB12 to an individual having hypothyroxinemia or another temporary periodof hypothyroidism. In yet another embodiment, the present inventionprovides a method of administering folate and vitamin B12 to anindividual that is a fetus or nursing child of a mother or caregiver whohas a thyroid-related medical condition.

In some embodiments, the present invention provides a composition of athyroid stimulating drug, a folate, and vitamin B12. This embodimentwill facilitate prevention and treatment of folate deficiencies forpersons that have hypothyroidism. In other embodiments, the compositionwill additionally include iron, and/or L-carnitine, and/or calcium,and/or vitamin D. In another embodiment, the present invention providesa composition of an anti-thyroid drug, a folate, and vitamin B12. Thisembodiment will facilitate prevention and treatment of folatedeficiencies for persons that are being treated for hyperthyroidism andmay also be complemented by iron, and/or L-carnitine, and/or calcium,and/or vitamin D.

In a preferred embodiment of the invention, the methods and compositionsfor prevention and treatment of thyroid-related medical conditions willrequire 5-methyltetrahydrofolic acid, or another reduced folate, andvitamin B12. In another preferred embodiment of the invention, thecomposition for prevention and treatment of thyroid-related medicalconditions will require 5-methyltetrahydrofolic acid, or another reducedfolate, and vitamin B12 with either an anti-thyroid drug or a thyroidstimulating drug. In another preferred embodiment, the composition ofanti-thyroid drug or thyroid stimulating drug, folate or another reducedfolate, and vitamin B12 will also comprise iron, and/or L-carnitine,and/or calcium, and/or vitamin D. With respect to calcium and vitamin D,these are the preferred embodiments that also address parathyroidhormone deficiencies.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

As used herein, “folate(s)” are a group of pteroyglutamate acids thatbecome structurally and functionally altered when reduced. The term“folate” refers to folic acid and any derivatives thereof.

Folic acid,(N-[4-(2-Amino-3,4-dihydro-4-oxo-6-pteridinylmethylamino)-benzoyl]-L-glutamicacid) also known as vitamin B9 or folicin as well asN-pteroyl-L-glutamic acid and N-pteroyl-L-glutamate, is a non-reducedfolate.

In humans, folates are absorbed most readily as the most active form6(R,S)-5-methyltetrahydrofolate (6(S)-5-methyltetrahydrofolate being themost biologically active) and it is the principal circulating form offolate (referred to herein as “reduced folate”). A nonexclusive list ofother reduced folates (also included in the definition of “reducedfolates”) are 10-methylenetetrahydrofolate, 10-formyltetrahydrofolicacid, 5-formyltetrahydrofolic acid, 5-forminino tetrahydrofolic acid,5,10-methenyltetrahydrofolic acid, 5,10-methyltetrahydrofolic acid,L-methylfolate, and 6(R,S)-5-formyltetrahydrofolate (folinic acid), andtetrahydrofolic acid/tetrahydrofolate.

The term of “folate” as referenced herein, is used as a genus, andgenerally refers to any of these forms of folate: folic acid, any formof reduced folates, and 5-methyltetrahydrofolic acid.

Vitamin B12, also called cobalamin, is a water soluble vitamin. VitaminB12 refers to a group of cobalt-containing vitamer compounds known ascobalamins: these include cyanocobalamin, hydroxocobalamin, and the twonaturally occurring cofactor forms of B12 in the human body:5′-deoxyadenosylcobalamin (adenosylcobalamin—AdoB12), the cofactor ofMethylmalonyl Coenzyme A mutase (MUT), and methylcobalamin (MeB₁₂), thecofactor of 5-methyltetrahydrofolate-homocysteine methyltransferase(MTR).

The term “cerebrospinal folate deficiency” (also referred to as cerebralfolate deficiency) is associated with low levels of5-methyltetrahydrofolate in the cerebrospinal fluid (CSF). In someconditions, the low levels of folate in CSF is also associated withnormal folate levels in the plasma and red blood cells. The onset ofsymptoms caused by the deficiency of folates in the brain generallybegin within the first year of life, but in the examples containedherein exhibited themselves at birth or within the immediate monthsthereafter. This is followed by delayed development, with decelerationof head growth, hypotonia, and ataxia, followed in many cases bydyskinesias (choreo-athetosis, hemiballismus), spasticity, and speechdifficulties, as well as numerous other cognitive, social, behavioral,psychological and physical conditions.

The term “masked megaloblastic anemia” is characterized by folate and/orvitamin B12 deficiencies occurring simultaneously with an irondeficiency, such that the iron deficiency masks the red blood cellindices changes of megaloblastic anemia.

The term “masked macrocytic anemias” refers to conditions where amacrocytic anemia is masked, and includes (a) masked megaloblasticanemia, (b) when a macrocytic anemia is masked by a microcytic tonormocytic anemia that occurs simultaneously with the macrocytic anemia,or (c) neutropenia that is masked at birth, in part, by a phenomenawhereby neutrophil counts and white blood cell values rise immediatelyafter birth.

The term “hypothyroxinemia” refers to conditions associated with thepresence of an abnormally low concentration of thyroxine in the blood.

The term “iron” as it relates to nutritional supplementation, refers toany form of iron that is generally known to supplement nutrition; forexample, an iron (II) salt, an iron (III) salt, or carbonyl iron.

The term “anti-thyroid drug” is a drug, agent or medication directedagainst the thyroid gland for the purposes of reducing thyroid function.The anti-thyroid drugs include, but are not limited to, carbimazole,methimazole, potassium perchlorate, and propylthiouracil (PTU). Thesedrugs are used to treat hyperthyroidism (overactivity of the thyroidgland) in order to reduce the excessive thyroid activity before surgeryand to treat and maintain patients not having surgery.

The term “thyroid stimulating drug” is a drug, agent, medication orhormone that acts as a replacement for a hormone that is normallyproduced by the thyroid_gland to regulate the body's energy andmetabolism. These drugs are used for the purpose of increasing thyroidfunction. thyroid stimulating drugs include but are not limited to:Levothyroxine, Levothyroxine Sodium, Liothyronine Sodium, Liotrix,Thyroglobulin, Thyroid, Thyroxine, Triiodothyronine Levoxyl, Synthroid,Levo-T, Unithroid, Levothroid, Levoxine, Levolet, Novothyrox, Triostat,Cytomel and Thyrolar.

The term “thyroid-related medical condition” refers to medicalconditions that arise when the thyroid gland is not functioningproperly. This could include hypothyroidism (under active thyroidfunction), hyperthyroidism (overactive thyroid function), anatomicaldisorders, and tumors (including thyroid cancer). “Thyroid-relatedmedical conditions” also arise from and include the use of agents, drugsor medications to treat the thyroid, or from environmental toxins orenvironmental conditions that impact the thyroid. The term“thyroid-related medical conditions” also includes complicationsassociated with diabetes mellitus, hypoparathyroidism and polyglandularfailure syndrome brought about in connection with a thyroid gland thatis not functioning properly.

II. Introduction

The present invention provides methods and compositions for preventionand treatment of thyroid-related medical conditions. The invention isbased on the discovery that an improperly functioning thyroid can causeharmful conditions. Some nonexclusive examples are cerebrospinal folatedeficiency and masked macrocytic anemias, and hepatic dysfunction. Theseconditions may be prevented or treated by the administration of folateand vitamin B12. Additionally there is a certain population ofindividuals who are also at risk for developing conditions that may betreated with the administration of folate and vitamin B12. Somethyroid-related medical conditions such as hypothyroidism andhyperthyroidism are treated with anti-thyroid drugs or thyroidstimulating drugs. Anti-thyroid drugs can cause harmful conditions suchas macrocytic blood disorders, which may be masked macrocytic anemias,as well as hepatic dysfunction, which itself may be idiosyncratic ordifficult to diagnose given its unpredictability and sudden onset. Theforegoing hematological and hepatic conditions can also lead tocerebrospinal folate deficiencies. As a result, the present inventionincludes a composition of these drugs with the addition of folate andvitamin B12.

III. Patient Population

For purposes of this invention patients are those who have beensuffering from thyroid-related medical conditions or those who are atrisk of suffering thyroid-related medical conditions, which thyroidconditions or risk of thyroid conditions may be caused by a number ofcircumstances, including, but not limited to, biological conditionswithin the patient's body, agents, drugs, or medications the patient hasbeen exposed to, or environmental exposure to toxins, or other adverseenvironmental conditions.

In one embodiment, the individual with a thyroid-related medicalcondition may suffer from hypothyroidism or hyperthyroidism. In general,hypothyroidism is a condition in which the thyroid gland does notproduce enough thyroid hormone. In general, hyperthyroidism is acondition in which the thyroid gland produces too much thyroid hormone.In a preferred embodiment, the patient is taking an anti-thyroid drug ora thyroid stimulating drug. While these types of patients may be at thehighest risk, other similar conditions pose a risk that may be treatedby the methods and compositions of this invention. For example, thosepersons with a thyroid-related medical condition and suffering from amacrocytic blood condition, masked megaloblastic anemia, maskedmacrocytic anemia or hepatic dysfunction, and those persons exposed toagents, drugs, medications, toxins and environmental conditions thatcause any of the foregoing hematological or hepatic conditions may betreated with the methods and compositions of this invention.

In another embodiment, the patient has a thyroid-related medicalcondition related to hypothyroxinemia.

In another embodiment, the patient may be any individual treated withradioactive iodine, or who has surgery on or related to the thyroidgland, or who undergoes any other process or procedure that alters thenormal function of the thyroid.

In another embodiment, the patient may be a fetus or newborn with amother or caregiver who has a thyroid-related medical condition.

IV. Detecting Conditions

a) Thyroid

One of the key discoveries of this invention is the discovery thatthyroid-related medical conditions can cause cerebrospinal folatedeficiencies, and the person with the thyroid condition is susceptibleto all of the harms associated with cerebrospinal folate deficiencies.In one embodiment, this invention treats persons with thyroid-relatedmedical conditions.

b) Hypothyroidism

In another embodiment, this invention treats persons withhypothyroidism. Hypothyroidism, or an improperly functioning thyroid,specifically not producing enough thyroid hormones, can lead to a personhaving cerebrospinal folate deficiencies. One of the aims of thisinvention is to treat people with hypothyroidism.

c) Hyperthyroidism

While it has been discovered that cerebrospinal folate deficiencies aremore commonly associated with hypothyroidism, persons withhyperthyroidism are also the subject of this invention because they takeanti-thyroid drugs to treat their hyperthyroid conditions. These drugshave the potential to lower the production of the thyroid to levels inwhich folate deficiencies may occur or to cause adverse macrocytichematological or adverse hepatic conditions leading to cerebrospinalfolate deficiencies. Therefore, hyperthyroidism is a condition relevantto this invention.

d) Diabetes, Hypoparathyroidism and Polyglandular Failure Syndrome

Thyroid-related medical conditions have been known to cause orcontribute to diabetes, diabetes mellitus, hypoparathyroidism andpolyglandular failure syndrome. Therefore, the conditions diabetes,diabetes mellitus, hypoparathyroidism and polyglandular failure syndromebrought upon by thyroid-related medical conditions are also the subjectof this invention.

e) Pregnant

Those who are pregnant and suffer from thyroid-related medicalconditions are also the subject of this invention, because the thyroidconditions a pregnant mother has can cause complications for the mother,as well as with the fetus and/or newborn.

f) Fetus

Because the complications of thyroid-related medical conditions may bepassed from the mother to the fetus, a fetus or newborn from a motherwith a thyroid-related medical condition is also the subject of thisinvention.

g) Nursing Child

Because the complications of thyroid-related medical conditions may bepassed through the milk of a nursing mother to the newborn, a newbornfrom a mother with a thyroid-related medical condition is also thesubject of this invention.

h) Hypothyroxinemia

Complications arising from thyroid-related medical conditions may alsoarise temporarily when a person is suffering from hypothyroxinemia.Periods of hypothyroxinemia have occurred during pregnancy in the motheror in the fetus. Even though this may be only a temporary period inwhich the thyroid is not properly functioning, harmful results may ariseduring this time. Therefore, hypothyroxinemia is also the subject ofthis invention.

i) Anti-Thyroid Drugs

A person taking anti-thyroid drugs is also the subject of thisinvention. It has been discovered that at times taking an anti-thyroiddrug can lower the function of the thyroid substantially enough to causecerebrospinal folate deficiency, for which this invention addresses. Inaddition, such agent, drug, or medication also causes adversehematological and hepatic conditions which can also lead tocerebrospinal folate deficiencies, for which this invention addresses.

j) Thyroid Stimulating Drugs

A person taking thyroid stimulating drugs is also the subject of thisinvention. As this invention addresses, hypothyroidism has been linkedto cerebrospinal folate deficiency. Prior to receiving a thyroidstimulating drug, a person has for the most part already suffered from athyroid-related medical condition. In certain cases, hypothyroidism isnewly discovered in an individual and during the period in which theindividual remained undiagnosed, the individual may have developeddeficiencies in folate or vitamin B12 or cerebrospinal folatedeficiency. In other cases, the individual may have been treated with ananti-thyroid drug for hyperthyroidism, and the drug caused theindividual to develop hypothyroidism, and the individual then suffersfrom adverse events not only related to the anti-thyroid medication (thecomplications of which have already been addressed herein), but also theadverse conditions of having hypothyroidism. In yet another example, theindividual has had hypothyroidism, but alternates between differentdegrees of hypothyroidism, such that the individual may be receiving atany given time an inadequate amount of thyroid stimulating drug, therebystill allowing the adverse complications of hypothyroidism to occur. Inall of the foregoing instances, this invention will prevent or treatsuch individual.

k) Radioactive Iodine, Surgery, or Any Other Method to Reduce the Sizeor Activity of the Thyroid Gland

The methods of this invention are also directed to a person who hasreceived radioactive iodine, or who has had surgery on or related to thethyroid gland, or who has had any other procedure that has reduced thesize and therefore the activity of the thyroid gland.

l) Hematological Conditions

It has also been discovered that macrocytic blood conditions, includingmasked macrocytic anemias may be brought upon by persons withthyroid-related medical conditions. As such this invention aims toprevent or treat the conditions brought upon through folate and vitaminB12 deficiencies in persons with masked macrocytic anemias.

m) Hepatic Dysfunction

It has also been discovered that hepatic dysfunction may be brought uponby persons with thyroid-related medical conditions, and in some cases,the hepatic dysfunction may be idiosyncratic or difficult to diagnosegiven its unpredictability and sudden onset. As such, this inventionaims to prevent or treat the conditions brought upon by folate andvitamin B12 deficiencies in persons with hepatic dysfunction.

V. Prevention Methods

While many of the uses of folate are generally well known, newconditions have been discovered that require the use of folates. It iswell known in the art that folate should be used for nutritionalsupplementation of pregnant and nursing mothers. This is due to the factthat folate is essential for DNA and RNA replication and therefore it isnecessary in growing and dividing cells, which are prevalent in nursingmothers and newborns. It is also known that folate, as well as vitaminB12, may be used to address neurological conditions, includingdepression. However, what was not known is that some thyroid-relatedmedical conditions can lead to cerebrospinal folate deficiencies.Therefore, it is the subject of this invention to disclose methods andcompositions of administering folate and vitamin B12 to thosesusceptible for developing cerebrospinal folate deficiencies andtherefore prevent the harmful, adverse conditions that arise from folatedeficiencies.

Some of the harmful conditions that arise from cerebrospinal folatedeficiencies affect development of fetuses and newborns. However,developmental problems are not limited to fetuses and newborns, as olderchildren, adolescents, young adults and adults can be affected as well.Some of the first symptoms associated with cerebrospinal folatedeficiencies are lower IQs and cognitive dysfunction. As the conditionprogresses, developmental delay, psychomotor regression, seizures,mental retardation, autistic features, behavioral issues and socialproblems may present themselves. As conditions worsen, physical functionis impaired. These are only a few of the conditions that may arise fromcerebrospinal folate deficiency brought upon through thyroid-relatedmedical conditions. The methods and compositions discussed herein willprevent and have been shown to alleviate and help correct thesesymptoms.

One embodiment of this invention provides a method to prevent harmfulconditions that arise from thyroid-related medical conditions. Thisembodiment comprises administering folate and vitamin B12 to peoplesuffering from such thyroid-related medical conditions.

Administration of the folate and vitamin B12 may be done in any manneralready known in the art.

In a preferred embodiment, this invention provides a method to preventand/or treat harmful conditions that arise from hypothyroidism.Hypothyroidism results in decreased thyroid function and decreasedhormone production, which regulates the endocrine system. It has beenrecently and surprisingly found that hypothyroidism can lead tocerebrospinal folate deficiency and all of the problems that arise fromdecreased folate levels. What is of even greater concern is that many ofthese patients suffering with cerebrospinal folate deficiency areinfants whose nervous system is still developing and lack folate at acrucial point in their development. In some cases, the damage cannot becompletely undone. Since the folate is deficient at such a crucialmoment in development, the adverse conditions can be severe. Oneembodiment of this invention is to administer folate and vitamin B12 topeople with hypothyroidism. This administration of folate and vitaminB12 will help to prevent problems and conditions that arise fromcerebrospinal folate deficiency.

In a preferred embodiment, a reduced folate is administered with vitaminB12 to a person with thyroid-related medical conditions. A non-exclusivelist of examples of reduced folates are: 10-formyltetrahydrofolic acid,5-formyltetrahydrofolic acid, 5-forminino tetrahydrofolic acid,5,10-methenyltetrahydrofolic acid, and 5,10-methyltetrahydrofolic acid.In a more preferred embodiment, 5-methyl tetrahydrofolic acid isadministered with vitamin B12 to persons with thyroid-related medicalconditions.

The amount of folate administered by the methods and compositions ofthis invention will depend upon the size, age, and severity of thecondition of the patient. Generally the National Institutes of Health,Office of Dietary Supplements (NIH) generally recommended dosageguidelines will suffice. This is also true for the administration ofvitamin B12, iron, calcium, vitamin D, and L-carnitine. In severe casesthe amounts may be increased. Dosage amounts may need to be lower thanNIH generally recommended dosage guidelines in the event of preventivemeasures, or in the event the patient is already taking supplementscontaining the foregoing, or in the event the patient is a prematureinfant or very newborn neonate.

In one embodiment, the amount of folate to be administered by themethods and compositions of this invention should be 0.5 mg to 0.1 mg offolate per kg of weight (of the patient) per day. In other cases, higherdosages of folate at 2-3 mg/kg/day are required to normalizecerebrospinal folate levels. Yet, in other cases, where preventivemeasures are being taken, or when the patient is a fetus, prematurenewborn or term neonate, then dosage amounts may be lower than theforegoing.

In one embodiment, the amount of reduced folate to be administered bythe methods and compositions of this invention should be 0.1 mg to 1.0mg of folate per kg of weight (of the patient) per day.

In a preferred embodiment, the amount of reduced folate to beadministered by the methods and compositions of this invention should be0.5 mg to 0.1 mg of folate per kg of weight (of the patient) per day. Inother cases, higher dosages of folate at 2-3 mg/kg/day are required tonormalize cerebrospinal folate levels. Yet, in other cases werepreventive measures are being taken, or when the patient is a fetus,premature newborn or term neonate, then dosage amounts may be lower thanthe foregoing.

The following tables are provided by the NIH as the recommended dietaryallowance for folate and other vitamins and minerals.

TABLE 1 Adequate Intake for Folate for Infants Age Males and Females(months) (μg/day) 0 to 6  65 7 to 12 80

TABLE 2 Recommended Dietary Allowances for Folate for Children andAdults Age Males and Females Pregnancy Lactation (years) (μg/day)(μg/day) (μg/day) 1-3 150 N/A N/A 4-8 200 N/A N/A  9-13 300 N/A N/A14-18 400 600 500 19+ 400 600 500

TABLE 3 Recommended Dietary Allowances (RDAs) for Vitamin B12 Age MaleFemale Pregnancy Lactation Birth to 6 months* 0.4 mcg 0.4 mcg 7-12months* 0.5 mcg 0.5 mcg 1-3 years 0.9 mcg 0.9 mcg 4-8 years 1.2 mcg 1.2mcg 9-13 years 1.8 mcg 1.8 mcg 14+ years 2.4 mcg 2.4 mcg 2.6 mcg 2.8 mcg

TABLE 4 Recommended Adequate Intake for Infants and Recommended DietaryAllowances for Iron for Infants (7 to 12 months), Children, and AdultsMales Females Pregnancy Lactation Age (mg/day) (mg/day) (mg/day)(mg/day) Infants 0.27 0.27 N/A N/A 7 to 12 months 11 11 N/A N/A 1 to 3years 7 7 N/A N/A 4 to 8 years 10 10 N/A N/A 9 to 13 years 8 8 N/A N/A14 to 18 years 11 15 27 10 19 to 50 years 8 18 27  9 51+ years 8 8 N/AN/A

TABLE 5 Adequate Intakes (AIs) for Calcium Age Male Female PregnantLactating Birth to 6 months 210 mg 210 mg 7-12 months 270 mg 270 mg 1-3years 500 mg 500 mg 4-8 years 800 mg 800 mg 9-13 years 1,300 mg 1,300 mg14-18 years 1,300 mg 1,300 mg 1,300 mg 1,300 mg 19-50 years 1,000 mg1,000 mg 1,000 mg 1,000 mg 50+ years 1,200 mg 1,200 mg

TABLE 6 Adequate Intakes (AIs) for Vitamin D Chil- Preg- Lac- Age drenMen Women nancy tation Birth to 13 years 5 mcg (200 IU) 14-18 years  5mcg  5 mcg 5 mcg 5 mcg (200 IU) (200 IU) (200 IU) (200 IU) 19-50 years 5 mcg  5 mcg 5 mcg 5 mcg (200 IU) (200 IU) (200 IU) (200 IU) 51-70years 10 mcg 10 mcg (400 IU) (400 IU) 71+ years 15 mcg 15 mcg (600 IU)(600 IU)

The recommended amount of L-carnitine to be administered is between 400mg and 3000 mg for adults, and 20 mg and 400 mg for children. Loweramounts may be necessary in preventative cases or premature/neonatecases.

While these ranges may be used as a guide, the best practice is for thephysician to determine the amount based upon the age, weight andseverity of the condition.

For example: a patient (later referred to as Example 2) sufferedcerebrospinal folate deficiency from birth until receiving treatmentmore than five years after birth. The child was treated with folinicacid at 5 mg twice per day. This dosage was necessary to address theextreme deficiency the child had developed starting in utero. In othercases, especially newborns, who may not have yet manifested any clinicalpresentations, lower allowances may suffice for prevention purposes.

In another example: a patient (later referred to as Example 1, and alsoa twin of Example 2) suffered from clinical signs of cerebrospinalfolate deficiency at birth. Example 1 received infant milk formula thatcontained vitamin B12. However, it was not until Example 1 received aseparate multivitamin nutritional supplement that contained 2 mcg ofvitamin B12 (500% more than the 0.4 mcg NIH recommended daily allowance)that Example 1 showed hematological response. As further addressed inthe Examples below, although Example 1 exhibited at birth and in themonths thereafter signs of cerebrospinal folate deficiency, over timethe damages Example 1 suffered as a result of cerebrospinal folatedeficiency were not as severe as Example 2. This is due to Example 1receiving additional vitamin B12 supplementation after birth andobtaining hematological response.

To the extent that this invention is treating a fetus, a prematurenewborn or a term neonate who may also be receiving adequate nutritionalsupplementation from other sources given such individual's then currentmedical status, trace amounts of folate and B12 can be sufficient toprevent the thyroid-related medical conditions. What is important is todetermine the total amounts of these vitamins from all of the mother'snutritional intake in determining the proper amounts to be administeredby this embodiment of the invention.

In another embodiment, this invention provides a method to preventand/or treat harmful conditions that arise from hyperthyroidism. Whileit is more common that folate deficiencies arise from hypothyroidism,patients with hyperthyroidism are also at risk due to the fact that theyare taking drugs that suppress thyroid function. The administration offolate, or reduced folates, and vitamin B12 will help prevent or treatproblems in conditions that arise when the thyroid is suppressed tolevels that will cause folate deficiency. One of the discoveries of thisinvention is that there are incidents where people who have been takinganti-thyroid drugs have taken an amount that actually lowered thethyroid function to below normal or that have adversely affected thehematological or hepatic conditions of the patient. A preferredembodiment of the invention prevents and/or treats the complicationsthat arise from such abnormal function. This preferred embodiment wouldcouple treatment of anti-thyroid drugs with the administration of afolate, or a reduced folate, and vitamin B12. In another embodiment,this administration may also be coupled with the administration of iron,L-carnitine, calcium or vitamin D, which may be administered by anymanner already known in the art.

In one embodiment, the condition that is a result of improper thyroidfunction is cerebrospinal folate deficiency. In another embodiment,masked megaloblastic anemia or a masked macrocytic anemia, or amacrocytic anemia is the condition that is a result of improper thyroidfunction. Both of these conditions have recently been linked to improperthyroid function. The present invention presents methods andcompositions to prevent and treat cerebrospinal folate deficiency andmasked macrocytic anemias that have arisen in patients with improperthyroid function.

In one embodiment, a folate and vitamin B12 are administered to preventmasked megaloblastic anemia or a masked macrocytic anemia, or amacrocytic anemia in a person that suffers adverse conditions as aresult of thyroid-related medical conditions. In cases of maskedmegaloblastic anemia or masked macrocytic anemia, or a macrocytic anemiathis administration may be coupled with the administration of iron. Theamount of iron necessary will be dependent upon the amount of ironanemia. It is to be cautioned, that overdoses of iron are also harmfuland could interfere with certain thyroid drugs' absorption rates. Inanother embodiment this administration may also be coupled with theadministration of calcium, yet, it should also be noted that calcium mayinterfere with the absorption rate of certain thyroid drugs. Both theiron and the calcium may be administered by any manner already known inthe art. In another embodiment, this administration may also be coupledwith the administration of L-carnitine or vitamin D, which may beadministered by any manner already known in the art.

In one embodiment, the condition that is a result of a thyroid-relatedmedical condition is hepatic dysfunction. In thyroid-related medicalconditions, the hepatic dysfunction can be idiosyncratic or difficult todiagnose given its unpredictability and sudden onset. The liver is oneof the major sites for folate and vitamin B12 storage and metabolism.The present invention provides methods and compositions to prevent andtreat the adverse effects caused by hepatic dysfunction, by theprovision of folate, or a reduced folate, and vitamin B12. In anotherembodiment, this administration may also be coupled with theadministration of iron, L-carnitine, calcium or vitamin D, which may beadministered by any manner already known in the art.

Another condition that results in improper thyroid function ishypothyroxinemia or other temporary period of hypothyroidism.Hypothyroxinemia is when a person suffers from an abnormally lowconcentration of thyroxine in the blood. Hypothyroxinemia has also beendiscovered to be linked to folate deficiency. In one embodiment of thisinvention, folate, or reduced folates, and vitamin B12 are administeredto a person with hypothyroxinemia to prevent and/or treat complicationsas a result of hypothyroxinemia. In another embodiment, thisadministration may also be coupled with the administration of iron,L-carnitine, calcium or vitamin D, which may be administered by anymanner already known in the art.

Many times when an individual is treated with radioactive iodine thisimpairs normal thyroid function. One embodiment of this inventionprevents and/or treats complications that arise from treatment withradioactive iodine through the administration of folate, or reducedfolates, and vitamin B12. Additionally, persons may undergo surgery onor related to the thyroid gland or have other medical procedures thatresult in the reduced size or activity of the thyroid. Complicationsarising from such treatments may be alleviated by the administration offolate, or reduced folates, and vitamin B12. In another embodiment, thisadministration may also be coupled with the administration of iron,L-carnitine, calcium or vitamin D, which may be administered by anymanner already known in the art.

A person who may be taking a thyroid stimulating drug to increase theamount of thyroid hormone may suffer conditions related to the naturallydecreased amount of thyroid hormone. In a preferred embodiment of theinvention, a folate, or a reduced folate, and vitamin B12 areadministered along with the thyroid stimulating drug to a person takinga thyroid stimulating drug. In another embodiment, this administrationmay also be coupled with the administration of iron, L-carnitine,calcium or vitamin D, which may be administered by any manner alreadyknown in the art.

Clinical conditions from abnormal thyroid function in pregnant ornursing women may be passed along to the fetus and/or later newborn. Oneembodiment of this invention will administer folate, or a reducedfolate, and vitamin B12 to these pregnant or nursing women. Somethyroid-related medical conditions prevent absorption and/or reductionof folates in pregnant women. Thus, even though a pregnant woman may betaking a prenatal vitamin supplement that includes a folate (generallyfolic acid), the thyroid-related medical conditions are preventing thebiologically active folates from reaching the fetus. Thus, the fetusthen suffers the adverse conditions from the thyroid-related medicalcondition of the mother. The embodiments of this invention, providingreduced folates to a pregnant woman with thyroid-related medicationconditions, will help prevent the fetus from suffering adverse effectsby providing the necessary reduced folates for development. In anotherembodiment, this administration may also be coupled with theadministration of iron, L-carnitine, calcium or vitamin D, which may beadministered by any manner already known in the art.

Additionally, other thyroid-related medical conditions can cause vitaminB12 deficiencies in pregnant women. Even if the mother is taking aprenatal vitamin with folates and/or vitamin B12, the thyroid-relatedmedical conditions can impair the mother's ability to reduce the folatesinto its biologically active form. Thus, the newborn suffers adverseconditions. The embodiments of this invention, provide vitamin B12 to apregnant woman with thyroid-related medication conditions and will helpprevent the fetus from adverse effects by providing the necessaryvitamin B12 to enable the reduction of folates needed for development.In another embodiment, this administration may also be coupled with theadministration of iron, L-carnitine, calcium or vitamin D, which may beadministered by any manner already known in the art.

Common treatment for thyroid conditions is the administration ofanti-thyroid drugs. An anti-thyroid drug is a hormone antagonist actingupon thyroid hormones. Examples include: propylthiouracil, methimazole,carbimazole, and potassium perchlorate.

Since people taking an anti-thyroid drug are susceptible to developingconditions related to decreased folate levels, one embodiment of thisinvention provides a composition which comprises an anti-thyroid drugcoupled with a folate, or a reduced folate, and vitamin B12.Administration of these nutrients along with the drug would prevent afolate deficiency from arising or treat a folate deficiency.

Propylthiouracil is a common anti-thyroid drug. Propylthiouracil is athioamide drug used to treat hyperthyroidism (including Graves disease)by decreasing the amount of thyroid hormone produced by the thyroidgland. PTU inhibits the enzyme thyroperoxidase. Propylthiouracil isclassified as Drug Class D in pregnancy. Class D signifies that there ispositive evidence of human fetal risk. Maternal benefit may outweighfetal risk in life-threatening situations. The primary effect on thefetus from transplacental passage of PTU is the production of a mildhypothyroidism when the drug is used close to term. This usuallyresolves within a few days without treatment. The hypothyroid state maybe observed as a goiter in the newborn and is the result of increasedlevels of fetal pituitary thyrotropin. In one embodiment, a compositionof propylthiouracil, folate, or a reduced folate, and vitamin B12 iscreated to be administered to people who need to take anti-thyroiddrugs.

Methimazole is another common anti-thyroid drug. In another embodiment,a composition of methimazole, folate, or a reduced folate, and vitaminB12 is created to be administered to people who need to takeanti-thyroid drugs.

This invention is not limited to the specific anti-thyroid drugs thatare mentioned, rather a composition of any anti-thyroid drug may becoupled with a folate, or reduced folate, and vitamin B12. In anotherembodiment, this administration may also be coupled with theadministration of iron, L-carnitine, calcium or vitamin D, which may beadministered by any manner already known in the art.

VI. Treatment Methods

Many embodiments of this invention require the administration of folate,or reduced folates, and vitamin B12. Folates are administered to treatthe folate deficiency created by the thyroid-related medical conditions.In one embodiment, folic acid is the folate that is administered withthe vitamin B12. Folic acid is not biologically active, but it is aneffective treatment for many people who have the ability to convertfolic acid into its tetrahydrofolate derivatives.

In some instances folic acid treatment is not enough as folic acid isnot the biologically active form of folate. Some individuals havedifficulty reducing folic acid into its more biologically active form,therefore, it is necessary to provide these individuals with a reducedfolate. A preferred embodiment of the invention is the administration ofa reduced folate with vitamin B12.

It is estimated that administration of a reduced folate with vitamin B12is sufficient to prevent and treat a large percentage of people withthyroid conditions. However, a material percentage must still receive5-methyltetrahydrofolic acid and vitamin B12 to adequately preventand/or treat the conditions brought upon by the folate deficiencies dueto thyroid-related medical conditions. This is the most preferredembodiment of the invention. Indeed, even if an individual's bloodlevels of folate are treated and brought to normal, if the degree offolate deficiency was significant or prolonged over a sustained periodof time such that the individual's folate stores were depleted, then thecerebrospinal folate levels will remain low despite normalization offolate levels in the blood.

Further, while in some cases the treatment of folate may be enough totreat the folate deficiencies, in other cases the administration ofvitamin B12 is essential. Vitamin B12 is essential for folates to becomebiologically active. It has been observed that one may suffercerebrospinal folate deficiency and yet have normal folate blood levels.That is because there is folate that is in the blood, however, becauseof the deficiency in vitamin B12, the folate does not becomebiologically active.

For example: Example 1 and Example 2 (as discussed below) were born anddiagnosed with hypothyroidism. Upon birth, Example 1 presented with moresevere clinical conditions than Example 2. However, Example 1 receivedan additional multivitamin nutritional supplement that included 2 mcg ofvitamin B12. Example 2 did not receive the same multivitamin nutritionalsupplement that included 2 mcg of vitamin B12. Approximately five yearsafter birth, Example 2 was tested for cerebrospinal folate deficiencyand was found to be deficient in cerebrospinal folate. Example 1 wastested approximately four months after Example 2's cerebrospinal folatetest and was normal in cerebrospinal folate values.

VII. Compositions

One embodiment of the invention includes a composition of ananti-thyroid drug, folate, and vitamin B12. In one embodiment of thisinvention, this composition would be administered to a pregnant womanwith hyperthyroidism. The anti-thyroid drugs could be any drug that hasbeen approved to treat an overactive thyroid gland or suppress thyroidfunction. A nonexclusive list includes: propylthiouracil, methimazole,carbimazole, and potassium perchlorate. The amounts of anti-thyroid drugwould be the amounts a physician would prescribe that is appropriate forthe patient's condition. The amount of folate should be at least 30% ormore of the generally recommended allowance by the NIH, depending onwhat additional supplements the patient may be taking. The amount ofvitamin B12 should be at least 30% or more of the generally recommendedallowance by the NIH, depending on what additional supplements thepatient may be taking. Dosage amounts may need to be increased ordecreased depending on such factors. For instance, with respect toExample 1 (as discussed above and below), 2 mcg of vitamin B12 per daywas required for Example 1 to show hematological improvement, whichequates to a 500% increase over NIH's recommended daily allowance. Thiscomposition may be administered by any means necessary already known inthe art. In a preferred embodiment, the composition would beadministered in a capsule containing all three elements. The capsulecould be made by any means necessary already known in the art.

The combination of an anti-thyroid drug and folate and vitamin B12 willserve to provide folate and vitamin B12 to the patient and preventfolate deficiencies including cerebrospinal folate deficiency. Thevitamin B12 is necessary to help the folate transport into the cerebralspinal fluid.

In a more preferred embodiment of the invention, a composition wouldinclude an anti-thyroid drug, a reduced folate, and vitamin B12. Theamount of reduced folate should be at least 30% or more of the generallyrecommended allowance of folic acid by the NIH, depending on whatadditional supplements the patient may be taking. Dosage amounts mayneed to be increased or decreased depending on such factors. Sincereduced folates are more biologically active, a reduced folate would bemore effective in treating folate deficiencies. Additionally, thoseindividuals who reduce folic acid would be benefitted by taking areduced folate. It is estimated that this composition would be effectivefor a significant percentage of persons with cerebrospinal folatedeficiency. For the remaining population, 5-methyltetrahydrofolic acidis necessary.

In a more preferred embodiment of the invention, a composition wouldinclude an anti-thyroid drug, 5-methyltetrahydrofolic acid, and vitaminB12. The amount of 5-methyltetrahydrofolic acid should be at least 30%or more of the generally recommended allowance for folic acid by theNIH. In another preferred embodiment, the amount of5-methyltetrahydrofolic acid should be based on a formula of 0.1-1.0mg/kg/day. Depending on what additional supplements, the patient may betaking, dosage amounts may need to be increased or decreased dependingon such factors.

Since other complications arise from thyroid-related medical conditions,another embodiment of this invention includes a composition thatincludes an anti-thyroid drug, a folate, vitamin B12, and/or iron,and/or L-carnitine and/or calcium and/or vitamin D. L-carnitine hasshown to improve mental development in cellular metabolism. Thesefunctions are necessary for those susceptible to folate deficiencies. Inaddition, Example 2 (described below) became hypothyroid as a result ofanti-thyroid drug treatment in the mother. At the time Example 2 wasdiagnosed with cerebrospinal folate deficiency, Example 2 also had adeficiency in L-carnitine. Anti-thyroid drugs have been shown to causehypothyroidism, and hypothyroidism causes iron deficiencies; therefore,iron supplements may be suitable to correct any iron deficiency.Further, to the extent the hyperthyroidism treatment causeshypothyroidism, hypothyroidism has been found to be associated withhypoparathyroidism. Calcium is effective in the treatment ofhypoparathyroidism, and vitamin D assists in the absorption of calcium.

In another embodiment of the invention, a composition would include athyroid-stimulating drug, folate, and vitamin B12. In one embodiment ofthis invention, this composition would be administered to an individualwith hypothyroidism. The thyroid-stimulating drug could be any drug orhormone that has been approved to treat underactive thyroid function. Anonexclusive list includes: Levothyroxine, Levothyroxine Sodium,Liothyronine Sodium, Liotrix, Thyroglobulin, Thyroid, Thyroxine,Triiodothyronine, Levoxyl, Synthroid, Levo-T, Unithroid, Levothroid,Levoxine, Levolet, Novothyrox, Triostat, Cytomel and Thyrolar. Theamounts of thyroid-stimulating drug would be the amounts a physicianwould prescribe that is appropriate for the patient's condition. Theamount of folate should be at least 30% or more of the generallyrecommended allowance by the NIH, depending on what additionalsupplements the patient may be taking. The amount of vitamin B12 shouldbe at least 30% or more of the generally recommended allowance by theNIH, depending on what additional supplements the patient may be taking.Dosage amounts may need to be increased or decreased depending on suchfactors. For instance, with respect to Example 1 (as discussed above andbelow), 2 mcg of vitamin B12 per day was required for Example 1 to showhematological improvement, which equates to a 500% increase over NIH'srecommended daily allowance. This composition may be administered by anymeans necessary already known in the art. In a preferred embodiment, thecomposition would be administered in a capsule containing all threeelements. The capsule could be made by any means necessary already knownin the art.

The combination of a thyroid-stimulating drug and folate and vitamin B12will serve to provide folate and vitamin B12 to the patient and preventfolate deficiencies including cerebrospinal folate deficiency. Thevitamin B12 is necessary to help the folate transport into the cerebralspinal fluid.

In a more preferred embodiment of the invention, a composition wouldinclude a thyroid-stimulating drug, a reduced folate, and vitamin B12.The amount of reduced folate should be at least 30% or more of thegenerally recommended allowance of folic acid by the NIH, depending onwhat additional supplements the patient may be taking. Dosage amountsmay need to be increased or decreased depending on such factors. Sincereduced folates are more biologically active, a reduced folate would bemore effective in treating folate deficiencies. Additionally, thoseindividuals who reduce folic acid would be benefitted by taking areduced folate. It is estimated that this composition would be effectivefor a significant percentage of persons with cerebrospinal folatedeficiency. For the remaining population, 5-methyltetrahydrofolic acidis necessary.

In a more preferred embodiment of the invention, a composition wouldinclude a thyroid-stimulating drug, 5-methyltetrahydrofolic acid, andvitamin B12. The amount of 5-methyltetrahydrofolic acid should be atleast 30% or more of the generally recommended allowance for folic acidby the NIH. In another embodiment, the amount of 5-methyltetrahydrofolicacid should be based on a formula of 0.1-1.0 mg/kg/day. Depending onwhat additional supplements the patient may be taking, dosage amountsmay need to be increased or decreased depending on such factors.

Since other complications arise from thyroid-related medical conditions,another embodiment of this invention includes a composition thatincludes a thyroid stimulating drug, a folate, vitamin B12, and/or iron,and/or L-carnitine and/or calcium and/or vitamin D. L-carnitine hasshown to improve mental development in cellular metabolism. Thesefunctions are necessary for those susceptible to folate deficiencies. Inaddition, Example 2 (described below) became hypothyroid as a result ofanti-thyroid drug treatment in the mother. At the time Example 2 wasdiagnosed with cerebrospinal folate deficiency, Example 2 also had adeficiency in L-carnitine. Hypothyroidism causes iron deficiencies;therefore, iron supplements may be suitable to correct any irondeficiency. Further, hypothyroidism has been found to be associated withhypoparathyroidism. Calcium is effective in the treatment ofhypoparathyroidism, and vitamin D assists in the absorption of calcium.

VIII. Examples

The following examples illustrate the medical conditions presented intwins who were born to a mother diagnosed with hyperthyroidism who hadexcessive anti-thyroid drug treatment during the pregnancy that, as aresult, created a hypothyroid state in the mother as well as ahypothyroid state in the twin neonates.

Example 1 and Example 2 were both infant patients.

Both Example 1 and Example 2 were born to a mother who was diagnosedwith hyperthyroidism and was treated with excessive anti-thyroid drugsduring the pregnancy, thus creating a hypothyroid state in the mother,and in the fetuses. It was later determined that both Example 1 andExample 2 were hypothyroid in utero.

Both Examples 1 and 2 received thyroid stimulating drugs after birth andbecame euthyroid within approximately one week of birth.

Immediately after birth, Example 1 had evidence of megaloblastic anemiaand neutropenia. Example 2 had evidence of masked megaloblastic anemia,as well as neutropenia that may have been masked. It is notable thatExample 2's hematological testing was performed approximately one hourafter Example 1's hematological testing, a period of time in whichneutrophil and white blood cell values have been shown to rise. BothExample 1 and Example 2 showed signs of hepatic dysfunction. It isnotable that the mother showed signs of idiosyncratic hepaticdysfunction during the pregnancy while taking anti-thyroid drugs.

Both Example 1 and Example 2 were treated for iron deficiencies withiron supplements.

Example 1 and Example 2 received different nutritional supplementationwith respect to vitamin B12. Although Example 2 did receive the sameinfant milk formula that Example 1 received, which infant milk formulacontained vitamin B12, Example 2 received less of the infant milkformula than Example 1, and Example 2 received in lieu of the infantmilk formula more of the breast milk from the hypothyroid mother.Example 1 also received an additional multivitamin nutritionalsupplement that included 2 mcg of vitamin B12. Example 2 received adifferent version of the multivitamin nutritional supplement that didnot include vitamin B12.

When Example 1 received the additional nutritional supplement containing2 mcg of vitamin B12, Example 1 showed prompt hematological response byan increase in reticulocytes, moving from below normal to normal, whichis evidence of a treated vitamin B12 and/or folate deficiency. Example2, however, showed regression in reticulocyte values and remained belownormal, evidencing a continued vitamin B12 and/or folate deficiency.

Both Example 1 and Example 2 exhibited signs associated withcerebrospinal folate deficiency at birth and within the ensuing year,including, but not limited to, failure to thrive, drowsiness, pallor,glossitis, sepsis and septicemia, as well as neurological manifestationsincluding cognitive impairment, movement disorders and peripheralneuropathy. For the most part, Example 2 exhibited more drastic versionsof the symptoms, including behavioral and social issues and painfulmovement disorders.

In summary, it has been determined that the proper maternal folatemetabolism, which was altered by the excessive anti-thyroid drugtreatment, the mother's hypothyroidism, and pernicious anemia,critically affected delivery of folate to the embryo and transport ofintact folate across the placenta. This means that Example 1 and Example2 began to suffer from systemic folate deficiency in the womb, andsystemic folate deficiency leads to cerebrospinal folate deficiency.Example 1's and Example 2's folate condition was also impacted by theirown hypothyroidism and placental transfer of the mother's anti-thyroiddrug. It is notable that the thyroid stimulating drugs that Example 1and Example 2 received immediately after birth and which brought each ofthem to a euthyroid state within approximately a week did notsufficiently address cerebrospinal folate deficiencies, nor was theprompt hematological response seen in Example 1 after additional vitaminB12 supplementation associated with the thyroid stimulating drugstreatment.

Both Example 1 and Example 2 displayed a number of conditions consistentwith cerebrospinal folate deficiency. Example 1 and Example 2 aresimilar in that both Example 1 and Example 2 had a mother treated withan anti-thyroid drug and that was diagnosed with hypothyroidism, therebyresulting in hypothyroidism in Example 1 and Example 2. Additionally,both Example 1 and Example 2 had goiters at birth, had similar labtreatment in the hospital after birth, and lived a somewhat similar life(food, upbringing, school, same medications and vitamin supplements,vaccinations, etc.) after discharge from the hospital. One significantdifference was that Example 1 received more vitamin B12 supplementationthan Example 2, and Example 1 showed prompt hematological response.

The Importance of Reduced Folates, Especially 5-Methyltetrahydrofolateor Folinic Acid

Although Example 1 suffered and continues to suffer from symptomsassociated with the onset of cerebrospinal folate deficiency, Example1's manifestations have been to a lesser degree than Example 2. Example2 has suffered, and continues to suffer, from symptoms of cerebrospinalfolate deficiency to a greater degree than Example 1.

Approximately five years and three months after birth, cerebospinalfolate levels were observed for the first time in Example 2. Example 1was tested for cerebrospinal folate deficiency approximately four monthsafter Example 2's testing. Example 1 showed normal levels ofcerebrospinal folate, which is consistent with the additional vitaminB12 support Example 1 received after birth (and the resultinghematological response), and the lesser degree of symptoms associatedwith the onset of cerebrospinal folate deficiency that Example 1 hassuffered from. Studies have shown that the earlier the anemiasassociated with cerebrospinal folate deficiency are addressed, thebetter the adversely impacted individual can overcome more long-termeffects of the associated folate deficiency. Notwithstanding Example 1'scerebrospinal folate deficiency test results, Example 1 still haspermanent neurological damage resulting from cerebrospinal folatedeficiency at birth, demonstrating the need for the methods andcompositions of this invention.

Example 2 showed below normal levels of cerebrospinal folate, which isconsistent with Example 2's lack of hematological response after birthgiven Example 2's lesser vitamin B12 supplementation, and the higherdegree of symptoms associated with cerebrospinal folate deficiency thatExample 2 has suffered from. After Example 2's diagnosis, Example 2 wasplaced on 5-methyltetrahydrofolate in the form of folinic acid (5 mgtwice per day). Within approximately four months, Example 2'scerebrospinal folate levels rose from 32 L (preferred range 40-128) toapproximately 88 (middle of the range). Thus after four months oftreatment, Example 2 achieved normal cerebrospinal folate levels, whileExample 2 could not achieve such normal levels within the first fiveyears of Example 2's life even when receiving multivitamins with folicacid and vitamin B12. Thus, reduced folates are critical.

After 5-methyltetrahydrofolate treatment, Example 2 showed improvementin physical, behavioral and social skills.

1. A method of treating decreased folate in cerebrospinal fluid,comprising: a. selecting an individual with hypothyroidism treated witha thyroid medication and who is in a medication induced euthyroid state;and b. administering a composition comprising a folate to theindividual.
 2. The method of claim 1, wherein the folate is a reducedfolate.
 3. The method of claim 2, wherein the thyroid medication is athyroid stimulating drug and the reduced folate is administered withvitamin B12 and the thyroid stimulating drug.
 4. The method of claim 3,further comprising the administration of one or more of the following:iron, L-carnitine, calcium, or vitamin D.
 5. The method of claim 2,wherein the reduced folate is in a composition comprising a thyroidstimulating drug, vitamin B12, and one or more of the following: iron,L-carnitine, calcium, or vitamin D.
 6. The method of claim 1, whereinthe folate is L-methylfolate.
 7. The method of claim 6, wherein thethyroid medication is a thyroid stimulating drug and the L-methylfolateis administered with vitamin B12 and the thyroid stimulating drug. 8.The method of claim 7, further comprising the administration of one ormore of the following: iron, L-carnitine, calcium, or vitamin D.
 9. Themethod of claim 6, wherein the L-methylfolate is in a compositioncomprising a thyroid stimulating drug, vitamin B12, and one or more ofthe following: iron, L-carnitine, calcium, or vitamin D.
 10. The methodof claim 1, wherein the folate is in a composition comprising a thyroidstimulating drug, vitamin B12, and one or more of the following: iron,L-carnitine, calcium, or vitamin D.
 11. The method of claim 1, furthercomprising the administration of vitamin B12 to the individual.
 12. Themethod of claim 1, wherein the individual has a masked megaloblasticanemia.
 13. The method of claim 1, wherein the individual has a maskedmacrocytic anemia.
 14. The method of claim 1, wherein the individual hasa macrocytic anemia.
 15. The method of claim 1, wherein the individualhas hepatic dysfunction.
 16. The method of claim 1, wherein theindividual had hypothyroxinemia.
 17. The method of claim 1, wherein theindividual had radioactive iodine or radiation that affected the thyroidgland, or had surgery on the thyroid gland.
 18. The method of claim 1,wherein the thyroid medication is a thyroid stimulating drug.
 19. Themethod of claim 1, wherein the individual has amethylenetetrahydrofolate reductase polymorphism.
 20. The method ofclaim 1, further comprising the administration of vitamin B12 and ironto the individual.
 21. The method of claim 1, further comprising theadministration of vitamin B12 and L-carnitine to the individual.
 22. Themethod of claim 1, further comprising the administration of vitamin B12and calcium to the individual.
 23. The method of claim 1, furthercomprising the administration of vitamin B12 and vitamin D to theindividual.
 24. The method of claim 1, wherein the composition furthercomprises vitamin B12 and one or more of the following: iron,L-carnitine, calcium, or vitamin D.
 25. The method of claim 1, whereinthe thyroid medication is a thyroid stimulating drug and the folate isadministered with vitamin B12 and the thyroid stimulating drug.